Project Summary/Abstract Drug addiction is a complex neuro-behavioral disorder, involving pharmacological, psychological and genetic influence. The dopamine receptor system plays a highly relevant role for mechanisms underlying reward and addiction. At the synaptic level, sensitization is mediated through dynamic mechanisms, such as receptor internalization; at the whole-brain level, adaptation is reflected through dynamic changes in brain signaling. These dynamic changes, and how drug exposure or treatment can alter them, are still not well understood in vivo but are a critical step towards improving treatment options and outcomes for substance abuse and related psychiatric disorders. The goal of this grant is to apply in vivo with multi-modal imaging in order to investigate how specific pharmacological interventions and stimulant drugs of abuse modulate receptor adaptation mechanisms of the dopamine receptor system, and test novel approaches to prevent such adaptation mechanisms. State-of-the-art integrated positron emission tomography (PET) with functional magnetic resonance imaging (fMRI) will be used to image receptor trafficking dynamics using drugs that are known to induce receptor internalization at D2/D3 dopamine receptors, and then measure these adaptations for stimulants drugs of abuse. Non-human primates will be imaged to establish dynamic relationships between receptor occupancy (PET) and functional activation (fMRI). Together with biophysical modeling, quantification of receptor trafficking rates and their influence on functional signaling will be quantified. Finally, the involvement of the glutamate receptor system will be tested as an approach to prevent receptor trafficking as induced by drugs of abuse. This approach will help unravel the action of drugs targeted at the dopamine systems and their role in the neurobiological evolution of the development, maintenance and eventual prevention and treatment of drug addiction.